Screening of diabetic patients for microalbuminuria in primary care--The PROSIT-Project. Proteinuria Screening and Intervention.

The PROSIT (Proteinuria Screening and Intervention) Project started in 1993 in order to obtain data on the prevalence of micro- and macroalbuminuria in diabetic patients treated in primary care, to establish an easy screening programme for microalbuminuria, in which also diabetic patients can participate in self-responsibility, and to implement a specific intervention programme for incipient nephropathy. In 58 representative doctor's offices 647 diabetic patients were included, who performed at home self-tests for microalbuminuria on three days within one week using the early morning urine and a newly developed qualitative immunologic test-strip for microalbuminuria. After storage they returned the same urine samples to their doctors' offices for semiquantitative retesting with the immunologic test-strip Micral-Test II. In case of positive results the proteinuria dipstick Combur-9-Test was applied in order to exclude other causes of positive microalbuminuria (e.g. urinary tract infection). Data of 569 patients (6% Type 1, 88% Type 2 and 6% secondary diabetes) could be analysed. Both qualitative self-testing for microalbuminuria at home and semiquantitative retesting in doctors' offices were found to be feasible. Based on semiquantitative retesting the prevalences of microalbuminuria (macroalbuminuria) were 19.6% (0%) in Type 1 diabetes, 17.2% (10.8%) in Type 2 diabetes and 11.7% (7.8%) in secondary diabetes. Type 2 diabetic patients showed a clear correlation between albuminuria and diabetes duration, HbA1c, serum creatinine, triglycerides as well as micro- and macrovascular complications. 227 patients with micro- or macroalbuminuria were included into the ongoing PROSIT intervention programme.     

Interferon therapy in malignant melanoma]

Recent clinical trials on the systemic application of various forms of interferon in metastatic malignant melanoma showed a moderate response rate of about 11% on an average. Intralesional application of alpha- and beta-interferon, however, resulted in partial or complete regression of the metastases in approx. 50% of the tumors. At present, various combination studies are being carried out in order to enhance the anti-tumor effects of interferon and thus establish a potential therapeutic method in dermato-oncology. In this respect, the combination of alpha-interferon with classic cytostatic drugs (dacarbazine and vindesine) is especially encouraging.     

p53-dependent integration of telomere and growth factor deprivation signals

Ectopically expressed hTERT enables p16(INK4A)(-) human mammary epithelial cells to proliferate in the absence of growth factors, a finding that has led to the hypothesis that hTERT has growth regulatory properties independent of its role in telomere maintenance. We now show that telomerase can alter the growth properties of cells indirectly through its role in telomere maintenance, without altering growth stimulatory pathways. We find that telomere dysfunction, indicated by 53BP1/phosphorylated histone H2AX foci at chromosome ends, is present in robustly proliferating human mammary epithelial cells long before senescence. These foci correlate with increased levels of active p53. Ectopic expression of hTERT reduces the number of foci and the level of active p53, thereby decreasing sensitivity to growth factor depletion, which independently activates p53. The continuous presence of hTERT is not necessary for this effect, indicating that telomere maintenance, rather than the presence of the enzyme itself, is responsible for the increased ability to proliferate in the absence of growth factors. Our findings provide a previously unrecognized mechanistic explanation for the observation that ectopically expressed hTERT conveys growth advantages to cells, without having to postulate nontelomeric functions for the enzyme.     

Prospective evaluation of supportive care with or without CVD chemotherapy as a second-line treatment in advanced melanoma by patient's choice: a multicentre Dermatologic Cooperative Oncology Group trial

This prospective, nonrandomized multicentre, phase III study compared best supportive care (BSC) alone with cisplatin, vindesine and dacabazine-based (CVD) chemotherapy and BSC in patients with advanced melanoma. A total of 117 pretreated patients with metastatic melanoma were evaluated, 34 patients in arm A (BSC) and 83 in arm B (BSC and CVD). Primary endpoint was overall survival and secondary endpoints were disease control rate and quality of life (European Organisation for Research and Treatment of Cancer QLQ-C30). Owing to sparse recruitment of patients for randomization, the protocol has been changed based on patients' choice. Baseline characteristics were imbalanced with respect to the Karnofsky Performance Index (P=0.001), the existence of brain metastases (P=0.035) and earlier application of chemoimmunotherapy (P=0.038). Disease control was observed in 8.8% of patients in arm A and in 28.9% of patients in arm B (P=0.028). Median overall survival time was 137 days in arm A and 229 days in arm B (P=0.014). Multivariate analyses could not ascribe this prognostic benefit to CVD treatment. No significant difference in the quality of life could be found. This study could not detect clear survival benefits for polychemotherapy with CVD compared with BSC alone in patients with advanced metastatic melanoma. Interestingly, having the choice of chemotherapy or BSC alone in a second-line situation, more than 70% of patients chose polychemotherapy.     

Sex differences in survival of cutaneous melanoma are age dependent: an analysis of 7338 patients

This study identified sex differences in clinical presentation and survival for primary cutaneous melanoma without clinical evidence of metastasis at diagnosis from 1976 to 2008 in southern Germany. Melanoma-specific survival curves and estimated survival probabilities were generated using the Kaplan-Meier method. Multivariate survival analyses were carried out using the Cox modeling. Male patients had significantly thicker and more frequently ulcerated tumors and a lower 10-year disease-specific survival (DSS) and recurrence-free survival probability compared with females among patients of 43 years old or younger (DSS: 86.1 vs. 93.2%, P<0.001) and 44-60 years old (DSS: 83.5 vs. 90.1%, P<0.001). The survival advantage of female patients in terms of 10-year DSS and 10-year recurrence-free survival was not observed after an age of 60 years (P=0.21 and 0.51, respectively). Sex was of prognostic importance for DSS and survival after recurrence [hazards ratio (HR): 1.3; 95% confidence interval (CI): 1.1-1.6; P=0.002 and HR: 1.2; 95% CI: 1.0-1.5; P=0.018, respectively]. Stratified by age groups, sex remained of prognostic importance for DSS only in patients of 43 years or younger, and 44-60 years old (HR: 1.5; 95% CI: 1.0-2.1; P=0.03 and HR: 1.4; 95% CI: 1.1-2.0; P=0.02, respectively). Sex is an independent prognostic factor in surviving melanoma. The sex difference in survival with a better outcome for women is confined to melanoma patients of 60 years and younger. In addition, in younger age groups, male patients present with prognostically unfavorable features of primary melanoma. A female survival advantage is also known for other solid tumors such as colon and lung cancer; however, age dependency has not been studied.     

Melanocytes in nevi and melanomas synthesize basement membrane and basement membrane-like material. An immunohistochemical and electron microscopic study including immunoelectron microscopy

Light microscopic studies have shown that nevus cell nests and melanoma nests are surrounded by basement membrane (BM) material containing type IV collagen and laminin. This study confirms this by electron microscopy and relates it to proteins which interact with the basement membrane. Nevi except for dysplastic and Spitz nevi, malignant melanomas, and melanoma metastases were studied by immunohistopathology, routine electron microscopy (EM), and immunoelectron microscopy. The lesions were incubated with monoclonal antibody (moAb) against type IV collagen, laminin, and the integrin alpha6 and studied by light microscopy. In addition, melanomas were studied by immuno-EM after incubation with a moAb against matrix metalloproteinase-2 (MMP-2). Nevus cell nests and melanoma nests are surrounded by BM material containing type IV collagen and laminin by immuno-EM. The BM material various in thickness and is amorphous. Type IV collagen, laminin, and MMP-2 are synthesized by melanoma cells as well as adjacent fibroblasts. Destruction or loss of the BM is not mandatory for melanoma invasion or even metastasis. Possibly the BM material is a protective wall for melanoma cells. Interactions between melanocytes and the extracellular matrix of which the BM is a part, can be traced back to the migration of melanocytes from the neural crest.     

The dermoscopic classification of atypical melanocytic naevi (Clark naevi) is useful to discriminate benign from malignant melanocytic lesions

BACKGROUND: The dermoscopic classification is a useful tool for handling patients with atypical naevi (Clark naevi). OBJECTIVES: To investigate if the dermoscopic classification of atypical naevi is of any value to discriminate benign from malignant melanocytic lesions. METHODS: Consecutive patients (n = 205) were included with 254 suspicious melanocytic lesions, confirmed by histopathology at the Pigmented Lesions Clinic of the Department of Dermatology, University Medical Center, University of Tuebingen, Germany. In this retrospective study, dermoscopic images of benign and malignant melanocytic lesions were classified according to the dermoscopic classification of atypical naevi (reticular, globular, homogeneous or combinations of two of these) and pigmentation (uniform, central hyper- or hypopigmentation, eccentric peripheral hyper- or hypopigmentation, or multifocal hyper- or hypopigmentation). The three-structure type (reticular, globular and homogeneous) was additionally defined. RESULTS: Reticular, homogeneous and reticular-homogeneous types were significantly more frequent in naevi than in melanomas, whereas the three-structure type was significantly more frequent in melanomas (P < 0.001). A sensitivity of 86.7%, specificity of 87.7% and diagnostic accuracy of 87.4% was obtained. Uniformly pigmented and centrally hyperpigmented types were significantly more frequent in naevi than in melanomas, whereas eccentric peripheral hyperpigmented and multifocal hyper- or hypopigmented types were significantly more frequent in melanomas (P < 0.001). CONCLUSIONS: The dermoscopic classification of atypical naevi (Clark naevi) is useful to discriminate benign from malignant melanocytic lesions. The three-structure type and eccentric peripheral hyperpigmentation were significantly more frequently found in malignant than in benign melanocytic lesions. The knowledge of these two dermoscopic types should be helpful for the management of patients presenting with multiple melanocytic lesions.